Study Endorses Levodopa for Parkinson’s Treatment

By Juliann Schaeffer

A study finding from the PD MED trial, the largest-ever trial of Parkinson’s disease (PD) treatment, which may come as a surprise to some physicians, showed that patients reported better mobility and overall quality of life when taking levodopa, PD’s old mainstay treatment drug, compared with newer (and more expensive) treatment options, such as dopamine agonists (DAs) and monoamine oxidase type B inhibitors (MAOBIs).

Adverse Effects Abound
While levodopa has been the most widely used treatment for PD for years, previous studies have shown that with long-term use, patients can develop dyskinesias (involuntary muscle spasms) and other movement issues. However, DAs and MAOBIs aren’t free of unwanted side effects either. While patients on these treatment alternatives are less prone to dyskinesias, they’re at higher risk for other side effects, including nausea, hallucinations, oedema, and sleep disturbances.

“The most common adverse effects of these treatments are daytime sleepiness, nausea (mostly initially), confusion (late in the disease or in those with fragile cognition to start with), and impulse control disorders,” says Connie Marras, MD, PhD, an associate professor of neurology at Toronto Western Hospital in Ontario, Canada.

“Dopamine agonists tend to have higher rates of all of these effects compared with levodopa, and levodopa tends to be the best tolerated of these medications,” she continues. “Levodopa is associated with a higher frequency of motor fluctuations and dyskinesias developing over time, but the initial treatment strategy has not been shown to result in significant differences in the rates of disabling dyskinesias developing over time.”

While unwanted side effects can unfortunately be expected with any of these standard PD treatments, Marras says it’s more common for patients to voluntarily stop a DA treatment regimen than levodopa due to its adverse effects. She notes, however, that it’s unlikely a patient would discontinue all PD medications because of adverse effects and then remain untreated.

According to PD MED study leader Richard Gray, a professor from the University of Oxford in the United Kingdom, researchers and physicians have been well aware for some time that levodopa treatment comes with a higher risk of dyskinesia as compared with DAs and MAOBIs—which is the reason many physicians recently have been passing over levodopa as an initial treatment option for newly diagnosed patients. “For this reason, clinicians have been reluctant to start treatment with levodopa and most patients, particularly younger patients, are given a dopamine agonist as initial treatment,” Gray says.

But Gray sees several limitations with many of the previous studies conducted on PD treatments, including small study populations and a focus on clinicians’ assessments of patients’ symptoms rather than patient reports of their overall quality of life. He hoped the PD MED trial would add new evidence to help frame physicians’ treatment recommendations, and he says the study results add clarity on the benefits and risks of the different treatment options for people with newly diagnosed PD.

“PD MED shows that fears about late complications with levodopa treatment are unfounded and that, despite more dyskinesia, the balance of benefits and risks favors levodopa for younger as well as for older patients,” he says. “Another surprising finding for many people is that starting treatment with MAOBI was at least as good as starting with dopamine agonists.”

PD MED Details
In the trial, published recently in The Lancet, 1,620 study participants with early PD were randomly assigned to receive levodopa or an alternate drug (DAs or MAOBIs). Median follow-up was three years, with some patients followed for up to seven years. After analyzing patients’ self-reported scores on the mobility subscale of the PDQ-39, a PD-specific health status questionnaire, researchers noted small but significant benefits to levodopa when it came to how patients perceived their mobility and quality of life during the course of their PD treatment.

According to study authors, levodopa patients reported more benefits than their levodopa-sparing counterparts in other areas such as activities of daily living, cognition, communication, and bodily discomfort scales.

“We found that when we asked patients with Parkinson’s disease how their drugs affected their overall quality of life, the older drug levodopa was better than newer, more expensive drugs and that this benefit persisted for at least seven years from starting treatment,” Gray says.

Marras says she isn’t surprised that the initial choice of treatment didn’t result in large differences over years of follow-up, given that physicians were free to change treatment over time in this naturalistic study. “However, it is interesting that a statistically significant difference in favor of initial levodopa treatment persisted even up to seven years of follow-up,” she says.

“It is unclear why this would be, but may reflect a reluctance to add on ‘sufficient’ levodopa in patients already on other treatments for Parkinson’s disease (the majority of patients on other treatments will require the addition of levodopa after several years) or may relate to differential dropout of patients across the treatment arms,” she adds.

Clinician Takeaway
So what do the study’s findings mean for clinicians’ strategies for PD treatment? And will it change the prescribing landscape from the way in which clinicians currently treat PD patients?

Marras says that in today’s clinical environment, the PD treatment approach is most often determined first by patient age. “In older patients, levodopa would be most commonly prescribed as initial treatment and remains the cornerstone of therapy throughout the course of the disease,” she says. “In younger patients [patients under the age of 60] dopamine agonists would be more commonly prescribed as initial therapy and then levodopa added some years into the course when more potent anti-Parkinson effect is needed or the patient fails to tolerate dopamine agonist therapy any longer.”

She notes that for clinicians considering treatment options for patients in the early stages of PD, potential side effects of treatment don’t typically come into play, “although monoamine oxidase inhibitors are generally thought of as less potent than the other two choices, so more severely affected patients would generally be treated with one of the other two,” she says. “In later stages, if the patient is experiencing motor fluctuations, MAOB inhibitors and dopamine agonists can be useful adjunctive therapy as they are longer acting.”

While she’s not convinced that this one study will alter the overall prescribing landscape of clinicians treating PD patients, Marras does believe this study will reassure physicians that initial treatment with levodopa offers a good strategy with little downside. “Previously, some physicians tended to avoid this due to the fear of motor fluctuations and dyskinesias, but initial treatment with levodopa does not appear to result in a meaningful increase in problems, at least when measured in terms of mobility,” she says.

Because the differences in mobility between the treatment groups were so small, Marras says it is questionable whether the differences would be meaningful to patients. However, she says the main take-home message that practitioners should glean from this study is that levodopa, DAs, and MAOBIs should all be considered reasonable initial treatment options. “The treatments differ in their side-effect profiles and their cost, and these aspects of the treatment choices may be the basis on which to base treatment choices rather than anticipated differences in efficacy,” she says.

According to Gray, this study cements the benefits of an older and cheaper PD treatment choice. “Although the differences in favor of levodopa are small, when you consider the short- and long-term benefits, side effects, quality of life for patients, and costs, the old drug levodopa is still the best initial treatment strategy for most patients,” Gray says.

“We already have feedback from UK participants in PD MED that their practice will change markedly with more use of levodopa and MAOB inhibitors and less use of dopamine agonists,” he adds.

More Challenges Ahead
Regardless of the treatment clinicians consider to be appropriate for their newly diagnosed PD patients, Marras and Gray agree research is needed to address remaining challenges in the treatment of PD.

“Some of the biggest challenges are cognitive impairment and progressive balance difficulties, as these are not effectively managed by current treatments,” Marras says. “We have mildly effective treatments for cognitive impairment [cholinesterase inhibitors] but need more effective agents or disease-modifying therapies.”

In addition, she notes that while balance difficulties are currently managed through the use of physical therapy and walking aids, greater access to exercise programs and physiotherapy is needed to prevent and address the progressive balance difficulties that inevitably appear with advancing disease.

In Gray’s opinion, the greatest challenge, as with any neurodegenerative disease, lies in identifying ways of slowing PD’s progress. More and longer studies would be beneficial in achieving that end, he says. “We need still longer follow-up of PD MED to see whether the benefits of levodopa and MAOBIs over the first few years increase over time,” he says, which would show whether the drugs are neuroprotective.

“The only reliable way to detect neuroprotective effects is very big long-term studies like PD MED, and we need more of these,” he continues. “Neurodegenerative diseases are poorly researched compared to, say, cancer or cardiovascular disease, and they are just as important.”

— Juliann Schaeffer is a freelance writer and editor based in Alburtis, Pennsylvania.